Drug Development by Leonardo Scapozza

This course proposes an overview of current global health challenges drawing on the insights of several academic disciplines including medicine, public health, law, economics, social sciences and humanities. This interdisciplinary approach will guide the student into seven critical topics in global health.

从本节课中

Research, Development, Innovation and Technology for Global Health

This module addresses the lack of attention to research and development for medicines and technologies for diseases that disproportionately affect developing countries and all the issues related to drug development and intellectual property rights.

与讲师见面

Rafael Ruiz De Castañeda

Institute of Global Health - Faculty of MedicineUniversity of Geneva

Antoine Flahault

Professor of Public Health and Director of the Institute of Global Health (Faculty of Medicine, University of Geneva) and co-Director of Centre Virchow-Villermé (Université Paris Descartes)University of Geneva and Université Paris Descartes – Sorbonne Paris Cité

[MUSIC]

Welcome to today's lecture on drug development within the week dedicated to

research development innovation and technology for global health.

Today I will try to give you an overview, what is drug development,

what are the challenges and what are the solutions eventually of these challenges.

So we will first start with a definition.

What is drug development?

Then we will look at the challenges, at the society level and

scientific level for continue

afterwards in trying to address this challenges by science.

At the end, we will conclude, we need a short outlook on the topic.

What is drug development?

As you can see here, there are two phases,

because drug development is a two step process composed by a discovery

phase which lasts usually around four to six years, and

a clinical development phase which last around six years.

Most phases and process at once, aim at discovering

new candidate medication and bring them to patient and to the market.

So the aim of drug development is to get an approved drug

from the regulatory body and to get these drugs to the patient.

Drug development has evolved through time.

Indeed, until 1880,

more or less, that means for 3,000 years.

People have practiced traditional medicine, or also called folk medicine.

This was the only source of drugs.

And how they get the drugs was about doing observation and serendipity.

And indeed, nowadays we would call this process as clinical studies.

So they were just trying to drop on the human being and see what happens.

1980, then there was the new coming of chemistry and

the human being being able of mastery chemists and

thereof the period of the classical drug development started,

which means a systematic search of new chemicals with biological activity.

The novelty in this period was the induction of animal models,

for mimicking human diseases.

When I say animal models in this period I am saying you take a wild type mouse.

You give a drug and you see what happens.

And this is where the famous in vivo studies as we call it nowadays.

During this period, major contributing scientific fields were chemistry,

pharmacology, microbiology, pharmaceutical sciences and biochemistry.

1980, the turnaround, molecular biology came in place.

The technique of molecular biology came in place.

And this changed completely the paradigm of discovering and developing drugs.

Target could be identified, could be expressed.

And instead of doing a systematic search based mostly on natural product.

There was a tactical search of new chemicals with biological activity.

Through the technology of molecular biology, new in vitro

target based and cell based assays have been developed and

high throughput capability came into place.

Animal models were refined and nowadays we have

animal models which are more suited to mimic the disease.

In human and thereof, nowadays, many more fields

of science are contributing to drug development and

these fields are molecular and structural biology,

genomic, protiomy, metabolomic, bioinformatics.

Additionally to the classical one that we have already in place

and during the classical drug development.

Modern drug development is a multiple step leading to drug approval.

As you can see from these slides, you can see the different steps.

We have target validation and target discovery,

lead optimization, towards selection of a candidate,

further development of a candidate in order to enter the clinical phase.

And for each step, we have results that can be expected.

From the target discovery and validation, targets are arising and

assays are arising.

From the lead discovery phase, hits, lead compounds are arising.

And from the lead optimization we have a developmental candidate that is arising.

At that point, all the results have to be summarized together

in order to select the candidate to push further in clinical trials.

The selected candidate will undergo a pre clinical, pharmacokinetic and

pharmacodynamic study.

And after these studies, it is immediate or not to clinical trial.

Clinical trials are divided into three major phases.

The first one is phase one, where safety is the major outcome that is tested.

A small number of patients, less than 20 patients are enrolled for

testing the safety of the compound.

A second phase is a clinical phase two, deals with safety and efficacy.

Always we've moderately or

rather small number of patients 20 to 40.

And if phase two is pass successfully,

the compound enter in phase three which is a comparative

study where the compound or the new treatment is compare to

the standard treatment of care available at the time.

All these steps need a multitude of scientific and

social competencies for achieving your aim,

which is getting a drug to the patient or

getting it approved by the regulatory body FDA

[INAUDIBLE] in order that it can go to the patient.

These steps are time and resource demanding and

the success rate is moderately low.

As you can see here, the discovery phase usually costs

around 340 million US dollar

whereas the clinical development phase costs around 470 million.

And this you can see in the perspective of success.

One in three project, you have a heat compound.

One in three projects give a candidate and unfortunately, you would say,

less than one compound out of ten candidate get approved.

But how to solve this problem?

That's what I will tell you now, but before entering that,

I would like also to picture you the situation,

what is the context which drug development is done.

And the first context is the social context which are the challenges.

We are right now in a period under pressure,

regulatory pressure, patent cliff, and

as you can see from the graphs,

there is a lot of money that is apparently lost.

Because of patent expiration.

And these are billions, what you see there.

And you see the loss is very, very important.

And the billions lost on the market are not coming back for developing new drugs.

High failure rate in clinical trials is another key word.

Lack of innovation.

Failure of the blockbuster model.

Pressure on pricing.

Low hanging fruits have gone.

So what was easy to do has been done.

Having seen this set of challenges.

Let's see what type of scientific challenges that we have to address.

And this graph, taken from the Nature Review Drug Discovery

publication, shows that we have a problem with efficacy.

The lack of efficacy cause a lot of failure.

The same is for toxicology.

The same is for clinical safety.

That's where we have to work on.

In contrast in 91, the pharmacokinetics and

bioavailability where the major problem of the new developed chemicals.

But as you can see, this problem could be addressed by strong scientific effort.

And nowadays, pharmacokinetic and bio availability,

it's not anymore the major responsible for failure in clinical trials.

Besides the scientific challenges there are also commercial challenges

which makes, nowadays, the product not being pursued further.

So how to address these changes.

By science, because the major problematic we have toxicity, clinical safety,

efficacy, are all related to the molecule, the target

on which the molecule is binding to, and thus to science.

So the solution is very easy.

We should choose the right target, choose the right screen.

Choose the right molecule and choose the right clinical trials.

And this will help us reducing risk and attrition and

what we have to keep in mind is that we need to be able to give this right choice.

So we need to be correctly educated in terms of education and research.

But how to do it?

So choose the right target, choose the right molecule,

choose the right clinical trials, choose the right essay.

And these are all key words.

But in the next slide you see that if we combine

cutting edge science and technology.

If you combine state of the art experience and

excellence, we will be able to address these challenges.

On the left you see a picture telling us who is needed and when it's needed.

So we start at the gene, we have to identify the target.

The target is found out and validated.

On the target you give compounds, you test the compounds.

That have been previously synthesized.

You have a lead.

You profile the lead to see whether this compound is acting only on your target or

also on other part of the cells.

You optimize the lead by chemistry and eventually you go and

do the pre-clinical study.

Profiling in vivo using mice and then animals.

And eventually the compound made it into the clinical trials.

And once the clinical trials are done, we will make it to the public,

to the patient.

And all these steps that you see in picture

need an interdisciplinary and intradisciplinary effort.

And this will need to functional global health system because

we will be able to provide new drugs for [INAUDIBLE] medical need.

The prerequisite for that is that we have educated,

specialized scientists able to communicate together despite different expertise.

But let's look at the last point clinical trial.

The clinical trial has to be designed in a smarter way.

In order to improve the outcome.

In order to enable the patient profit from it.

If you look at the upper side of the slides

you'll see how this was done in the past.

A drug was developed.

A cohort of patients was chosen.

And then the question raised is which patient responds to the drug.

But if now we have the tools to do it now possibly.

We can determine the molecular profile of the patient and

then determine which drug can profit to which patient.

This paradigm is the paradigm of the personalized medicine,

which is not to be confused with, one drug for one person.

No, it's the right drug for the right court of patients.

And the [INAUDIBLE] goes with

this principle using the right marker to determine,

to stratify the patient that can profit from the developed

drug in this targeted search of drug with higher efficacy and

lower toxicity, which means higher clinical safety.

By that I'm almost at the end of my presentation and

it would give you some conclusion, take home message and an outlook.

I hope that in this 50 minutes I could

convince you that drug development is a pillar for global health

because it provides novel therapeutics to address unmet medical needs.

I hope also that you could be convinced that drug development is a very

challenging, difficult, time and resources demanding process with high failure risk.

That research and scientific education is essential to overcome societal and

scientific challenges.

That do educated choices based on detailed scientific knowledge of

the human system and personalized medicine will help reducing the risk and

increasing the success rate with our involvement.

And hopefully with a possible reduction of cost allow us to

address unmet medical need also in area of the neglected disease.

And what's important, and this is maybe not exactly the natural science,